A surprising shift (Outlook Magazine; June 2014)

Three promising biomarkers being studied to detect Alzheimer’s disease in its early stages appear to undergo a surprising shift as patients develop symptoms of dementia, researchers at Washington University School of Medicine in St. Louis report.

Scientists use the biomarkers to assess brain changes linked to the disease in research volunteers. The levels of markers of neuronal injury increase in the spinal fluid for a decade or more before the onset of dementia, but in a new twist, the research shows for the first time that they later reverse course, decreasing as symptoms of memory loss and mental decline appear.

“We’re not sure why this reversal occurs, but understanding it may be very important for clinical trials of drugs to treat or prevent Alzheimer’s,” said senior author Anne Fagan, PhD, research professor of neurology. “Changes in the levels of these biomarkers likely will be among the criteria we use to assess the success or failure of Alzheimer’s drugs, so we need to know how these biomarkers normally behave in the absence of treatment.”

Motivated by the realization that Alzheimer’s damages the brain for a decade or more before it causes dementia, researchers have identified several biomarkers of the disease in patients before they develop symptoms. They hope to use the biomarkers to diagnose patients and start treatment long before the onset of problems with memory and other brain functions that characterize dementia.

Fagan and her colleagues studied data from the Dominantly Inherited Alzheimer’s Network (DIAN), a multinational research project led by Washington University. All DIAN participants come from families affected by genetic mutations that cause rare inherited forms of Alzheimer’s. Carriers of their family’s mutation can develop symptoms of mental decline as early as their 30s.

DIAN participants regularly are evaluated using a variety of tests, including analyses of Alzheimer’s biomarkers in their spinal fluid. For the new study, Fagan and her coauthors looked at three injury-related biomarkers in spinal fluid samples collected at multiple evaluations of 26 DIAN participants. All the participants had an Alzheimer’s-causing mutation.

Two of the biomarkers, tau and p-tau, are structural proteins that form the neurofibrillary tangles seen in the brains of Alzheimer’s patients; the third is a neuronal calcium sensor called VILIP-1. Levels of the three biomarkers increase after neurons are injured and are linked to decline of cognitive function. Evidence suggests that as Alzheimer’s assaults the brain, dying cells release the biomarkers, freeing them to be washed into the spinal fluid.

HPAN: A BioMed 21 IRC

The Hope Center Program on Protein Aggregation and Neurodegeneration (HPAN) is the most formalized of the Hope Center Research Groups. HPAN, led by Director David Holtzman, is one of five Interdisciplinary Research Centers (IRCs) based in the new BJC Institute of Health. This group focuses on the shared mechanism of protein aggregation that underlies numerous neurological disorders. Read more about HPAN....